This randomized phase III trial studies bortezomib, lenalidomide, and dexamethasone to see how well they work compared to carfilzomib, lenalidomide, and dexamethasone in treating patients with newly diagnosed multiple myeloma. Bortezomib and carfilzomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Lenalidomide may help the immune system kill abnormal blood cells or cancer cells. Drugs used in chemotherapy, such as dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether bortezomib, lenalidomide, and dexamethasone are more or less effective than carfilzomib, lenalidomide, and dexamethasone in treating patients with multiple myeloma

PRIMARY OBJECTIVES:

I. To compare the overall survival between two strategies of lenalidomide maintenance following induction with a proteasome inhibitor? immunomodulatory drug (IMiD) combination: limited duration of maintenance (24 months) versus indefinite maintenance therapy until disease progression.

II. To compare progression-free survival between bortezomib, lenalidomide, and dexamethasone (VRd) and carfilzomib, lenalidomide, and dexamethasone (CRd) induction followed by lenalidomide maintenance in patients with newly diagnosed symptomatic multiple myeloma.

SECONDARY OBJECTIVES:

I. To compare the progression-free survival between two strategies of lenalidomide maintenance following induction with a proteasome inhibitor?IMiD combination: limited duration of maintenance (24 months) or indefinite maintenance therapy until disease progression.

II. To compare induction rates of response between VRd and CRd arms. III. To evaluate time to progression, duration of response and overall survival between VRd and CRd induction therapy.

IV. To compare induction rates of toxicity between VRd and CRd arms. V. To evaluate toxicity during lenalidomide maintenance. VI. To compare minimal residual disease (MRD) negative rates between VRd and CRd arms at end of induction therapy.

TERTIARY OBJECTIVES:

I. To compare the short and long-term health-related quality of life impact between the two strategies of lenalidomide maintenance.

II. To compare the impact on health-related quality of life between VRd and CRd induction therapy.

III. To evaluate the association between early induction response and change in health-related quality of life.

IV. To describe changes in health-related quality of life during the induction, active maintenance and observation phases.

V. To evaluate correlation between treatment adherence during maintenance and health-related quality of life.

VI. To compare MRD negative rates between the two strategies of lenalidomide maintenance.

VII. To compare MRD negative rates between VRd and CRd arms during induction therapy.

VIII. To examine patterns of change in MRD levels over time and examine conversion from detectable to MRD negative status.

IX. To evaluate agreement and association between International Myeloma Working Group (IMWG) and MRD based disease-free status.

X. To describe the mutational profile of newly diagnosed multiple myeloma. XI. To identify mutations associated with resistance to VRd and CRd induction therapy.

XI. To identify expression profiles associated with MRD negative status with each induction therapy.

XII. To determine the ability of MRD status at induction end to predict short-term and long-term overall and progression-free survival.

XIII. To determine the effects of tobacco, operationalized as combustible tobacco (1a), other forms of tobacco (1b), and environmental tobacco exposure (ETS) (1c) on provider-reported cancer-treatment toxicity (adverse events [both clinical and hematologic] and dose modifications).

XIV. To determine the effects of tobacco on patient-reported physical symptoms and psychological symptoms.

XV. To examine quitting behaviors and behavioral counseling/support and cessation medication utilization.

XVI. To explore the effect of tobacco use and exposure on treatment duration, relative dose intensity, and therapeutic benefit.

OUTLINE:

INDUCTION: Patients are randomized to 1 of 2 treatment arms.

ARM A: Patients receive bortezomib subcutaneously (SC) or intravenously (IV) on days 1, 4, 8, and 11 of courses 1-8 and days 1 and 8 of courses 9-12; lenalidomide orally (PO) daily on days 1-14; and dexamethasone PO daily on days 1, 2, 4, 5, 8, 9, 11, and 12 of courses 1-8 and days 1, 2, 8, and 9 of courses 9-12. Treatment repeats every 3 weeks for 12 courses in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive carfilzomib IV over 30 minutes on days 1, 2, 8, 9, 15, and 16; lenalidomide PO daily on days 1-21; and dexamethasone PO on days 1, 8, 15, and 22. Treatment repeats every 4 weeks for 9 courses in the absence of disease progression or unacceptable toxicity.

MAINTENANCE: After completion of induction therapy (or completion of at least 6 courses in Arm A but stopped early due to unacceptable toxicity, or at least 4 courses in Arm B but stopped early due to unacceptable toxicity), patients are then randomized to 1 of 2 maintenance treatment arms.

ARM C: Patients receive lenalidomide PO daily on days 1-21. Treatment repeats every 4 weeks for 24 courses in the absences of disease progression or unacceptable toxicity.

ARM D: Patients receive lenalidomide PO daily on days 1-21. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 3 years, and then annually for 10 years.

Inclusion Criteria:

• STEP I: Patients must be diagnosed with symptomatic standard-risk multiple myeloma (SR-MM) as defined by all of the following (except gene expression profile [GEP]70 status if unknown):

  • No evidence of t(14;16) by fluorescence in situ hybridization (FISH) testing on bone marrow or not available

  • No evidence of t(14:20) by FISH testing on bone marrow or not available

  • No evidence of deletion 17p by FISH testing on bone marrow

  • FISH should be from within 90 days of registration

    • NOTE: If the FISH result states that no immunoglobulin heavy chain (IgH) abnormality is present, both t(14;16) and t(14;20) can be considered negative; in addition, if the patient has a t(11;14) or t(4;14) translocation present, they can be considered negative for t(14;16) and t(14;20); if testing for t(14;16) or t(14;20) could not be performed for lack of sufficient material or non-availability of the probe in the test panel, patients can be enrolled on the study

  • Standard Risk GEP70 signature within the past 90 days (only if GEP has been done and results are available)

    • NOTE: GEP testing is NOT a requirement for the study; if the test has been done, patients found to have a GEP70 status of high-risk will not be eligible

  • Serum lactate dehydrogenase (LDH) =< 2 x upper limit of normal (ULN) within the past 28 days

  • No more than 20% circulating plasma cells on peripheral blood smear differential or 2,000 plasma cells/microliter on white blood cell (WBC) differential of peripheral blood within the past 90 days

    • NOTE: This is NOT the plasma cell % from the marrow aspirate

• STEP I: Patients must have measurable or evaluable disease as defined by having one or more of the following, obtained within 28 days prior to randomization:

  • >= 1 g/dL monoclonal protein (M-protein) on serum protein electrophoresis

  • >= 200 mg/24 hours (hrs) of monoclonal protein on a 24 hour urine protein electrophoresis

  • Involved free light chain >= 10 mg/dL or >= 100 mg/L AND abnormal serum immunoglobulin kappa to lambda free light chain ratio (< 0.26 or > 1.65)

  • Monoclonal bone marrow plasmacytosis >= 30% (evaluable disease)

  • Serum protein electrophoresis (SPEP), urine protein electrophoresis (UPEP), and serum free light chain (FLC) assay are required to be performed within 28 days prior to randomization; a bone marrow biopsy and/or aspirate is required within 28 days if bone marrow is being followed for response

    • NOTE: UPEP (on a 24-hour collection) is required, no substitute method is acceptable; urine must be followed monthly if the baseline urine M-spike is >= 200 mg/24 hr; please note that if both serum and urine M-components are present, both must be followed in order to evaluate response
    • NOTE: The serum free light chain test is required to be done if the patient does not have measurable disease in the serum or urine; measurable disease in the serum is defined as having a serum M-spike >= 1 g/dL; measurable disease in the urine is defined as having a urine M-spike >= 200 mg/24 hr

• STEP I: Hemoglobin >= 8 g/dL (obtained within 28 days prior to randomization)

• STEP I: Untransfused platelet count >= 75,000 cells/mm^3 (obtained within 28 days prior to randomization)

• STEP I: Absolute neutrophil count >= 1000 cells/mm^3 (obtained within 28 days prior to randomization)

• STEP I: Calculated creatinine clearance >= 30 mL/min (obtained within 28 days prior to randomization)

• STEP I: Bilirubin =< 1.5 mg/dL (obtained within 28 days prior to randomization)

• STEP I: Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) and serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) < 2.5 times the upper limit of normal (obtained within 28 days prior to randomization)

• STEP I: Patients must have received no more than one cycle (4 weeks or less) of prior chemotherapy and no more than 160 mg of prior dexamethasone (or equivalent dose of prednisone) for treatment of symptomatic myeloma; they should not have been exposed to lenalidomide, bortezomib or carfilzomib for treatment of symptomatic myeloma; prior radiation therapy to symptomatic lesions is allowed provided there are no residual toxicity related to radiation and blood counts that meet the study requirements

• STEP I: Prior systemic glucocorticoid use for the treatment of non-malignant disorders is permitted; prior or concurrent topical or localized glucocorticoid therapy to treat non-malignant comorbid disorders is permitted

• STEP I: Patients must not have active, uncontrolled seizure disorder; patients must have had no seizures in the last 6 months

• STEP I: Patients must not have uncontrolled intercurrent illness including uncontrolled hypertension, symptomatic congestive heart failure, unstable angina, uncontrolled cardiac arrhythmia, uncontrolled psychiatric illness or social situation that would limit compliance with the study, or a prior history of Stevens Johnson syndrome

• STEP I: Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2 (performance status [PS] 3 allowed if secondary to pain)

• STEP I: Patients with monoclonal gammopathy of undetermined significance or asymptomatic multiple myeloma are not eligible

• STEP I: Patients must not have grade 2 or higher peripheral neuropathy by Common Terminology Criteria for Adverse Events (CTCAE) 4.0

• STEP I: Patients must not have active, uncontrolled infection

• STEP I: Patients may have a history of current or previous deep vein thrombosis or pulmonary embolism but must be willing to take some form of anti-coagulation as prophylaxis if they are not currently on full-dose anticoagulation

• STEP I: Patients should not have New York Heart Association classification III or IV heart failure or myocardial infarction within the previous 6 months

• STEP I: Patients with a history of prior malignancy are eligible provided they were treated with curative intent and do not require active therapy (currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma ?in situ? of the cervix or breast are not excluded)

• STEP I: Females of childbearing potential (FCBP)* must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10-14 days prior to and again within 24 hours of starting lenalidomide and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking lenalidomide throughout the entire duration of study treatment, and for 28 days after the last dose of lenalidomide; FCBP must also agree to ongoing pregnancy testing; all patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure; female subjects must agree to use contraception or abstinence for 30 days after last dose of carfilzomib

  • A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months

• STEP I: Sexually active males must be willing to use a condom (even if they have undergone a prior vasectomy) while having intercourse, while taking lenalidomide and for 28 days after stopping lenalidomide; male subjects must also agree to abstain from donating blood, semen, or sperm during study participation and for at least 28 days after discontinuation from lenalidomide; male subjects must be willing to use condoms for 90 days after discontinuation of carfilzomib

• STEP I: The following patients will be excluded:

  • Pregnant women
  • Nursing women

• STEP I: Human immunodeficiency virus (HIV) infection is not excluded; known HIV positive patients must meet the following criteria:

  • Cluster of differentiation (CD)4 cell count >= 350/mm^3
  • No history of acquired immune deficiency syndrome (AIDS)-related illness
  • Not currently prescribed zidovudine or stavudine

• STEP I: Patient enrolling to this study must agree to register to the mandatory RevAssist program, and be willing and able to comply with the requirements of RevAssist

• STEP II: Patients must have complete induction without experiencing progression or patients must have received at least 6 cycles on Arm A and 4 cycles on Arm B but stopped induction therapy due to adverse events

• STEP II: Step 2 registration must be within 6 weeks of completing step 1 therapy

• STEP II: Patients must not have received any non-protocol therapy outside of the assigned induction therapy including stem cell transplant

• STEP II: ECOG performance status 0, 1, or 2 (PS 3 allowed if secondary to pain)

• STEP II: Any adverse event related to step 1 therapy must have resolved to grade 2 or less

• STEP II: Hemoglobin >= 8 g/dL (within 28 days prior to randomization to Step II)

• STEP II: Platelet count >= 75,000 cells/mm^3 (within 28 days prior to randomization to Step II)

• STEP II: Absolute neutrophil count >= 1000 cells/mm^3 (within 28 days prior to randomization to Step II)

• STEP II: Calculated creatinine clearance >= 30 mL/min (within 28 days prior to randomization to Step II)

• STEP II: Bilirubin =< 1.5 mg/dL (within 28 days prior to randomization to Step II)

• STEP II: SGPT (ALT) and SGOT (AST) < 2.5 times the upper limit of normal (within 28 days prior to randomization to Step II)

• STEP II: Females of childbearing potential (FCBP)* must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10-14 days prior to and again within 24 hours of starting lenalidomide and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking lenalidomide throughout the entire duration of study treatment, and for 28 days after the last dose of lenalidomide; FCBP must also agree to ongoing pregnancy testing; all patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure

  • A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months

• STEP II: Sexually active males must be willing to use a condom (even if they have undergone a prior vasectomy) while having intercourse, while taking lenalidomide and for 28 days after stopping lenalidomide; male subjects must also agree to abstain from donating blood, semen, or sperm during study participation and for at least 28 days after discontinuation from lenalidomide; males must agree to use contraception and agree to not donate sperm for at least 90 days after the last day of carfilzomib

• STEP II: The following patients will be excluded:

  • Pregnant women
  • Nursing women

• STEP II: Patient enrolling to this study must agree to register to the mandatory RevAssist program and be willing and able to comply with the requirements of RevAssist